Uncovering Aging Genes in Human Blood with Integrative Epigenetics

The DNA methylation data generated in this study (MGB500 cohort) have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession code GSE246337. The MGB4K DNA methylation data are available under restricted access for reasons of patient privacy and consent; access can be obtained through the Mass General Brigham Biobank (https://biobank.massgeneralbrigham.org/). The Generation Scotland (GS) DNA methylation data are available under restricted access due to consent restrictions and can be applied for via the GS Access Committee (https://www.ed.ac.uk/generation-scotland/for-researchers/access). Publicly available datasets used in this study include: MESA (DNA methylation and RNA-seq; dbGaP accession phs001416.v3.p1), PPMI (DNA methylation and RNA-seq; https://www.ppmi-info.org), GC6 RNA-seq (GEO GSE94438), 500FG RNA-seq (GEO GSE134080), JenAge RNA-seq (GEO GSE103232, GSE75337), RA DNAm (GEO GSE42861), Grady DNAm (GEO GSE132203), and GENOA DNAm (GEO GSE157131). The source data underlying the figures in this manuscript are provided in the accompanying Source Data file. We thank the staff of the Mass General Brigham Biobank for assistance with sample procurement. Funded by grants from the National Institute on Aging (NIA) and the Hevolution Foundation (M.M., V.N.G.). K.Y. is supported by an NIA K00 grant (Ref: K00AG088431). GS DNAm was primarily funded through Wellcome Trust support (reference 104036/Z/14/Z, 220857/Z/20/Z; R.E.M.). Additional funding came from: a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (Ref: 27404; awardee: D.M.H.); a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh (Awardee: H.C.W.); and a NARSAD Independent Investigator Award from the Brain & Behavior Research Foundation (Ref: 21956; awardee: K.L.E.). The Chief Scientist Office of the Scottish Government and the Scottish Funding Council (HR03006) provided core support for Generation Scotland (R.E.M.). Generation Scotland also received a grant from the Scottish Government Health Department, Chief Scientist Office (Number CZD/16/6; R.E.M.). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award Stratifying Resilience and Depression Longitudinally (STRADL) Reference 104036/Z/14/Z; R.E.M.). Ethical approval for the GS:SFHS study was obtained from the Tayside Committee on Medical Research Ethics (on behalf of the National Health Service). Author notes These authors contributed equally: Mahdi Moqri, Kejun Ying, Jesse R. Poganik, Chiara Herzog. Authors and Affiliations Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA Mahdi Moqri, Kejun Ying, Jesse R. Poganik, Alexander Tyshkovskiy, Alec Eames, Dmitrii Glubokov, Benyamin Matei-Dediu, Ludger Goeminne, Wayne Mitchell & Vadim N. Gladyshev Stanford University, Stanford, CA, USA Kejun Ying & Michael P. Snyder European Translational Oncology Prevention and Screening Institute, Universität Innsbruck, Innsbruck, Austria Chiara Herzog Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Qingwen Chen & Jessica A. Lasky-Su Northeastern University, Boston, MA, USA Mehrnoosh Emamifar Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK Jure Mur, Daniel L. McCartney & Riccardo E. Marioni Henri Mondor Hospital, Créteil, France Benyamin Matei-Dediu Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA Lucas A. Salas Contributions M.M., K.Y., J.R.P., and C.H. contributed equally to study design, data analysis, and manuscript preparation. M.M. and V.N.G. conceived and supervised the project. K.Y. and J.R.P. curated and integrated multi-omic datasets. C.H. contributed to statistical analyses and interpretation. Q.C. and J.A.L.-S. contributed to cohort design and data access. M.E., A.T., A.E., J.M., D.G., B.M.-D., L.G., and W.M. contributed to data processing and figure preparation. D.L.M., L.A.S., R.E.M., and M.P.S. contributed to external validation datasets and interpretation. All authors discussed the results, contributed to writing, and approved the final version of the manuscript. Corresponding authors Correspondence to Mahdi Moqri or Vadim N. Gladyshev. Competing interests M.M., M.P.S., K.Y., and V.N.G. have filed a patent on measuring cellular aging. R.E.M. is a scientific advisor to the Epigenetic Clock Development Foundation and has received consultancy fees from Optima Partners. D.L.McC is employed by Optima Partners in a part-time capacity. JLS is a scientific advisor for Precion Inc, Alamar, and TruDiagnostic. JLS has a sponsored research agreement with TruDiagnostic. The remaining authors declare no competing interests. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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